This is a competitive renewal of an R29 award in which the Principal Investigator has found that inhibition of complement with C-1 esterase inhibitor or soluble complement receptor type I has consistently attenuated I/R injury in animals. In the R29 portion of the preliminary work, the Principal Investigator has demonstrated that specific inhibition of C5a or inhibition of C5a and C5b-9 also decrease infarct size, neutrophil infiltration and apoptosis following myocardial I/R. The PI notes that myocardial vascular endothelium appears to be the site of initial complement activation during reperfusion. The global goal of the current investigations is to delineate the role of complement in myocardial I/R injury and to characterize the molecular mechanisms of complement activation during myocardial I/R.